Other than nicotine replacement therapy (NRT), bupropion is the only FDA-approved treatment for ! smoking cessation. Despite significant research into bupropion's mechanism of action, the specific sites responsible for its biological activity are still not fully understood. The mechanism of antidepressant action appears to be associated with long-term effects on noradrenergic neurons with some contribution from dopaminergic neurons. These changes likely occur by its activity at the dopamine and norepinephrine transporters, DAT and NET, respectivly. In vitro and in vivo pharmacological studies also indicate bupropion as well as its active metabolite (2S,3S)-hydroxybupropion is an antagonist of nicotinic acetylcholine receptors (nAChR), with the _41_2 nAChR subtype identified as the most relevant. Most research into bupropion's mechanism of action have focused on its transporter activity. However, we believe the clinical efficacy of bupropion for smoking cessation (and possibly depression) depends on its interaction with multiple molecular targets, which we term a Mulitple Target Model (MTM) of activity. Our specific hypothesis is that clinical efficacy of bupropion is achieved via iteractions with the c_4132nAChR and either or both the DAT and NET. Our main objective in Project 1 is to design, synthesize and assay targets compounds based on our bupropion MTM. In addition, data from our experiments should lead to a better understanding of the MTM and lead to the development of tools to further investigate nicotine addiction. The proposed targets of bupropion action are monoamine transporters, the c_41_2nAChR, and possibly other as yet undefined nAChR subtypes. This program project will involve systematic analysis of effects of various types of compounds on monoamine uptake and nAChRs and of effects of the compounds on behaviors related to nicotine dependence. This study will determine the mixture of targets that are features of this Multiple Target Model (MTM). The initial specific aims of this Project 1 are: (1) to design and synthesize target compounds from the bupropion and 3-phenyltropane classes for evaluation in monoamine uptake studies in this project as well as ot4_2 nAChR in Project 2 and in vivo studies proposed in Project 3;(2) to analyze initial in vitro and in vivo data from all three projects in an interative process to select compounds for evaluation in advanced in vivo models of nicotine withdrawal, drug discrimination, and self-administration in Project 3 designed to assess the potential of these compounds to be smoking cessation medications;and (3) to subject the complete data set to a statistical analysis to determine the targets that best correlate with the advanced in vivo studies and to propose the compounds for future development.